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The current developments of geopolitical rivalry, pandemic disruptions, and techno-nationalism have led to a fundamental reconfiguration of the global economic order, creating strategic imperatives for the multinational enterprises (MNEs) that go beyond the traditional internationalization theory. This paper aims to contribute to the literature with a systematic review of the adaptation process of MNEs in the time of geopolitical fragmentation and deglobalization. We used PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology to screen 200 initial records from Web of Science, Scopus, ScienceDirect, and JSTOR databases, resulting in 47 peer-reviewed articles, mostly published in the last eight years (2018–2026), and a few seminal articles from the past 30 years of international business studies. The analysis of our themes indicates that there are six main strategic response clusters: (1) reconfiguration of the supply chain, including reshoring, nearshoring, and friend-shoring; (2) geopolitical risk management via real options and diversification; (3) a renewed focus on regionalization over global integration; (4) digitalization as a strategic buffer; (5) nonmarket strategies, such as political adaptation and lobbying; and (6) de-internationalization, including staged divestment. We combine these themes into an integrative conceptual framework by integrating the EDGES themes (Economic Systems, Digital Disruptions, Geopolitical Fracture, Environmental Sustainability, and Socio-Cultural Ideology) with firm-level dynamic capability responses and performance outcomes. We find certain gaps that are of critical importance: lack of micro-level empirical evidence, lack of MNE perspectives from the emerging markets, and limited integration of artificial intelligence and geopolitics. The review contributes to the international business theory and provides practical guidelines for the management of MNEs in an increasingly fragmented world economy.